Most types of epileptic seizures, including induced generalized or focal seizures, except absence seizures, can be treated and prevented with diphenylhydantoin (DPH), which is also commonly called phenytoin, and other antiepileptic hydantoins.
DPH has the following structural formula ##STR1##
DPH usually exerts antiepileptic activity without causing general depression of the central nervous system. It can limit the development of maximal seizure activity and reduce the spread of the seizure process from an active focus.
Antiepileptic preparations containing DPH (and other antiepileptic hydantoins) are available in solid (oral) and liquid (oral and injectable) forms; they contain from 30 to 250 mg of DPH per unit dose.
The effectiveness of DPH increases with dosage. However, DPH is also toxic. Most of its toxic effects increase with dosage, length of exposure, and vary with the mode of administration.
Dose-dependent toxic effects associated with chronic use of DPH and other hydantoins include cerebellar vestibular effects (nystagmus, ataxia, diplopia, vertigo, etc.) and other central nervous system disturbances (blurred vision, mydriasis, hyperactive tendon reflexes, etc.), behavioral changes (hyperactivity, confusion, dullness, drowsiness and hallucinations), increased frequency of seizures, peripheral neuropathy, gastrointestinal distress, gingival hyperplasia, osteomalacia, megaloblastic anemia (that can be fatal), hirsutism, endocrine effects, lymphadenopathy et al. At very high doses (especially when administered intravenously), DPH can also cause cardiovascular collapse and/or general depression of the central nervous system.
DPH is not the only antiepileptic drug. A variety of other antiepileptic agents are known. Unfortunately, many of them also have undesirable toxic and side effects. Moreover, most known antiepileptic agents are effective for only selective types of seizures.
Accordingly, there is a need in the field for development of an anticonvulsant agent that would cause as few and as mild toxic and side effects as possible and yet be effective against a wide variety of seizure types. More specifically, there is a need for an anticonvulsant agent that would be effective at doses that minimize dose-related side effects against a variety of seizures.
In Mol. Pharmacol., 23:619-628 and 23:629-640 (1983) Craviso, G. L. and Musacchio, J. M. reported that dextromethorphan (DM), a nonnarcotic, nonaddictive, antitussive agent, had distinct binding sites in the cental nervous system, which were different from the binding sites for opiate compounds. The same investigators found that the binding of DM was effectively inhibited in vitro by a number of nonnarcotic centrally active antitussives (including certain DM analogs), certain phenothiazine neuroleptics, as well as some other compounds such as selective antidepressants, antihistamines, and muscarinic agents (i.e. agents that bind to the muscarinic receptor). They also found that the in vitro binding of DM to the central nervous system was markedly increased in the presence of certain compounds such as DPH and noscapine, but they were unable to predict which compounds would enhance DM binding and which would not. The authors proposed that research be conducted to determine whether DPH is an antitussive (or whether DM is an anticonvulsant), but that statement is at best a proposal for experimentation and does not suggest the method or the compositions of the present invention. Specifically, the anticonvulsant activity of DM can not be deduced or suggested from the disclosure of these references. In addition, the fact that DPH increases the binding of DM does not suggest that one would potentiate activity of the other, much less that DM would potentiate DPH activity.
It has now been discovered that DM and several other compounds that bind to the same sites in the brain possess substantial anticonvulsant activity in vivo. More important, it has been unexpectedly discovered that DM and these other compounds vigorously potentiate the anticonvulsant activity of DPH in vivo when administered simultaneously (or consecutively) with DPH. As a result, the minimum effective dose of DPH (and consequently its dose-dependent side-effects) can be substantially decreased. The potentiating effect is present even at subthreshold levels of DM (or the other compounds that bind to the same CNS sites).
Dextromethorphan (D-3-methoxy-N-methylmorphinan) has the following structural formula: ##STR2## It is sold as an antitussive in various liquid, resin, and solid antitussive dosage forms containing from 5 to 30 mg/5 ml of DM (or the equivalent), together with alcohol and/or other carriers and active ingredients used in management of cough and other symptoms of the common cold.
Although DM is a potent antitussive, it has no analgesic or addictive properties. Unlike codeine to which it is structurally related, it rarely produces drowsiness or gastrointestinal disturbances and has low toxicity (Goodman & Gilman's, The Pharmacological Basis of Therapeutics, Sixth Ed., MacMillan Publishing Co., New York 1980).
Therefore, use of DM (and other relatively innocuous compounds that compete with DM for the same CNS binding sites) to potentiate DPH will result in a substantial decrease in the dose-and exposure-dependent side effects of DPH with a concomitant enhancement (or without a compromise) in anti-seizure activity.